Can a patient with normal total testosterone, high Sex Hormone-Binding Globulin (SHBG), and low free testosterone safely start Testosterone Replacement Therapy (TRT)?

Testosterone Replacement Therapy for Patients with Normal Total Testosterone, High SHBG, and Low Free Testosterone

Testosterone replacement therapy (TRT) can be safely initiated in patients with normal total testosterone but high SHBG and low free testosterone, as this represents a state of reduced testosterone bioactivity despite normal total levels. 1

Understanding the Clinical Scenario

When evaluating testosterone status, it's critical to consider the relationship between total testosterone, free testosterone, and SHBG:

• Total Testosterone: Includes both bound (to SHBG and albumin) and free testosterone
• Free Testosterone: The unbound, biologically active fraction (1-2% of total)
• SHBG: A binding protein that reduces testosterone bioavailability

High SHBG levels can bind more testosterone, leaving less free testosterone available for biological activity, which can result in hypogonadal symptoms despite normal total testosterone levels 2.

Evidence Supporting TRT in This Scenario

Research demonstrates that high SHBG levels, independent of total testosterone, are associated with both subjective and objective androgen deficiency features 1. This indicates that a form of hypogonadism due to lower biological activity of testosterone does exist, even when total testosterone appears normal.

The American Urological Association (AUA) guidelines acknowledge that SHBG significantly affects the relationship between total and free testosterone, and failing to consider SHBG when interpreting testosterone levels may lead to misinterpretation 2.

Pre-Treatment Evaluation

Before initiating TRT, ensure:

1. Confirm low free testosterone: Verify with at least two morning measurements 2
2. Document symptoms: Assess for hypogonadal symptoms (decreased libido, erectile dysfunction, fatigue, decreased muscle mass, etc.)
3. Rule out contraindications: Particularly prostate cancer, severe lower urinary tract symptoms, erythrocytosis, or desire for fertility 3
4. Evaluate for secondary causes of high SHBG: Including hyperthyroidism, liver disease/cirrhosis, advanced age, HIV infection, and malnutrition 2

Treatment Approach

When initiating TRT in this scenario:

• Start with standard dosing: Begin with recommended doses of testosterone formulations (transdermal or intramuscular) 4
• Target normal free testosterone levels: Aim for free testosterone in the mid-normal range (50-200 pg/mL) 2
• Monitor response: Assess symptom improvement and laboratory parameters

Monitoring and Follow-up

Regular monitoring is essential:

• Testosterone levels: Check total and free testosterone at 3-6 months initially, then annually once stabilized 2
• Hematocrit/hemoglobin: Monitor at baseline, 3-6 months, and then annually; reduce dose or temporarily discontinue if hematocrit exceeds 54% 2
• PSA: Follow the same schedule as men without testosterone deficiency; consider increasing frequency of testing 3
• Symptom assessment: Evaluate improvement in hypogonadal symptoms

Special Considerations and Potential Risks

1. Fertility concerns: TRT suppresses spermatogenesis and should be discontinued well in advance of planned conception 3
2. Cardiovascular risk: Evidence regarding cardiovascular risk with TRT is mixed; the TOM trial was stopped early due to excess cardiovascular events, though other studies show potential metabolic benefits 3, 5
3. Prostate health: Current evidence does not link TRT to increased prostate cancer risk, but appropriate monitoring is still recommended 3
4. Metabolic effects: TRT may improve some components of metabolic syndrome, particularly in men with the lowest baseline testosterone levels 5

Common Pitfalls to Avoid

• Ignoring SHBG levels: Failing to consider SHBG when interpreting testosterone results can lead to missed diagnoses of functional hypogonadism 2
• Relying solely on total testosterone: Total testosterone alone is insufficient to assess androgen status when SHBG is altered 1
• Inadequate monitoring: Failing to monitor hematocrit regularly during treatment increases risk of complications 2
• Overlooking fertility concerns: Not discussing potential impact on fertility before initiating treatment 3

By carefully evaluating the patient's hormone profile and symptoms, and implementing appropriate monitoring, TRT can be safely initiated in patients with normal total testosterone but high SHBG and low free testosterone, potentially improving quality of life and reducing symptoms of hypogonadism.